ARBIOS developed a novel liver support therapy (SEPET) to treat patients with severe acute liver failure (ALF). In the absence of any other alternative, such patients must receive a liver transplant or endure prolonged hospitalization with greater than 80 percent mortality. In treating severe ALF it is critical to provide rapid and complete blood detoxification. For many years, it was assumed that toxins, which cause coma in hepatic failure, are small (<5 kDa) dialyzable molecules. Today, the repertoire of putative toxins that accumulate in the blood as a result of liver failure and necrosis includes also protein-bound toxins, cytokines and other <100 kDa molecules. These toxins damage not only brain, but also liver and inhibit its function and regenerative capacity. Of all the strategies employed to date for the development of blood detoxification systems, only total plasma exchange therapy was shown to be clinically effective in reversing hepatic coma and improving blood coagulopathy. However, this measure has not achieved wide clinical use because a large volume (up to 20 liters) of normal plasma is needed to produce desired clinical effects. SEPET stands for "selective plasma exchange therapy," i.e., for elimination of the "toxic" fraction of the patient's plasma rather than the entire volume of the patient's plasma. The goal of this proposal is to validate the SEPET concept. Plasma filters with 100 kDa molecular weight cut-off will be used. Pigs with surgically induced ALF will be subjected to 6-hour-long SEPET at the rate of 6 ml/min; normal homologous plasma will be used to replace the "toxic" fraction. In the control ALF pigs, whole plasma exchange using macroporous (0.2 micron) filters will be carried out for 6 hours at the rate of 6 ml/min. Survival time and changes in intracranial pressure, cerebral perfusion pressure, and standard liver function tests will be examined. The Company believes that the proposed studies will validate the SEPET concept and would help commercialize this novel therapy for nearly 250,000 patients with liver failure, which are hospitalized each year in the United States.